Heparin was invented accidentally by a 26 year old , Jay McLean, a pre clinical medical student in 1916 .It was one of the greatest discovery in medicine .It helped us prevent blood from clotting.Frozen blood inside human circulatory system constituted one of important mechanisms of human death.This ranged from acute myocardial infarction to cerebral thrombosis .

As we decoded the mechanism of action of heparin , it was clear it bound to the naturally occurring molecule antithrombin 3 and effectively blocks the intrinsic coagulation mechanism and thus behaves as an important anticoagulation agent.

There is a constant , delicate balance between procoagulant , anticoagulant and antifibrinolytic molecules .Intra vascular clots occur when a vascular injury triggers a clot formation and the clinical event occurs.

But, once insulted , the circulating blood does not remain a silent spectator . It is constantly on the look out for a foe to attack the thrombus that is interfering with its natural flow . Antithrombin 3 is one such molecule. Success of lysis depends on the power of natural forces. There are hundreds of episodes of microlysis that take place every day (Which happen without our knowledge ) .In patients with vascular disease these episodes are likely to be further more.

What does Intravenous heparin in high doses do ?

Heparin immediately blocks of powerful procaogualtion activity .One of the important heamatological principle is “Thrombus begets thrombus “. It is a vicious cycle. This is immediately tackled by heparin .The powerful trigger of thrombus induced thrombus propogation is shut off .

This makes a 2 cm sized clot to remain in 2cm . After making sure of this , the blood in the immediate vicinity start percolating the clot. The heparinised blood switches to a pro- fibrinolytic mode as the balance of forces is fully tilted in favor of fibrinolysis or thrombolysis.

Is there clinical evidence to call heparin as thrombolytic agent ?

Yes . Contrary to the popular scientific principle we have only clinical evidence . laboratory evidence is not convincing as heaprin lyses clot only in vivo . Since , evidnece based medicine requires laboratory evidence we hesitate to call this as thrombolytic agent !

It has been a strong clinical observation , many major intracardiac or intravascular clots regress in size

(or totally dissolve ) with intensive heparin regimen .The effect is seen in 48-72 hours.Some times in first 24 hours.

What are the clinical situations where heparin has successfully lysed the clots*?

Pulmonary embolism

LV clot

LA clot

Cortical venous thrombus

Deep vein thrombosis

Coronary thrombosis**

Portal vien thrombois

Renal vein thrombois

* Plenty of case reports available for each condition

** Sustained micro thrombolysis is the major mechanism of benefit in NSTEMI

If it is true , heparin dissolves thrombus , why it is not called as thrombolytic agent ?

Why not ? You decide yourself !

How does heparin compares with the great thrombolytic agents* like Strepotiknase, Urokinase,Altepase, Retepalse , Teneckteplase (TNK TPA) ?

Many (Rather most . . .) would consider it , as foolish , to compare heparin with these agents .But the fact of the matter is except for streptokinase there is no comparison studies available. Attempting such a study in humans will be considered unethical. Without a proper scientific data heparin can not be ignored either.

But , some of the control groups in major studies of thrombolysis through some light !

In pulmonary embolism thrombolytic agents and heparin have similar effects on intrapulmonary thrombus

An important point to remember here is , the powerful thrombolyic agents are administered in as short duration (Bolus / 1 hour infusion ) .This is invariably followed by heparin infusion . Why do we do that ? because we know it is important . One may never know , how much of lysis is done by the trhombolytic agent and how much by heparin .

if you analyse the data success rate of thrombolytic agents are infact attributable to the follow up heparin

Thrombolytic agents piggy packs on heparin and claims the credit for thrombolysis *

In thrombolytic therapy , heparin is considered as an adjunct to streptokinsae but in reality streptokinase may an adjunct to heparin

Importance of heparin In Acute MI (HEAP Trial)

It should be realized there is a time window for heparin too . . . early administration can have great benefit

Early heparin prevents formation of core of the clot .The importance of acute administration of aspirin in suspected STEMI is well recognized by paramedics . A bolus of heparin (10000 u) immediately could have great impact on the outcome as well .Paradoxically we talk more about emergency PCI, on transit TPA etc . . . We have seen number of patients referred with STEMI from suburban areas traveling for hours with out any anticoagulants but promptly getting sorbitarate tablets ! Unfortunately prehospital heparin is rarely stressed in literature .

Watch the video : Heparin : The forgotten hero

Final message

Heparin is an under rated drug as a thrombolytic agent.

Just because it has no direct action on thrombus it is considered an inferior agent.( One other reason for it to be considered inferior , it is very cheap !)

It’s usage should be early and liberal , especially in out of hospital setting in vascular emergency.

Note of caution : This article is not meant to defame the thrombolytic agents.It only stresses a point that , heparin has also a role , as a thrombolytic agent. *Whenever rapid thrombolysis is required in life threatening situations specific thrombolysis is indicated as per guidelines.

Cardiovascular system consists not only of heart but also the blood delivery and retrieval system namely the arterial and venous circulation .As the heart pumps , 6 liters of blood every minute , it has to traverse the entire venous circulation promptly , to complete the hemodynamic circuit.

Source : From web. Thanks to whoever created this Image

While physicians are preoccupied with disease of heart there is an important groups of disorder of venous system .The deep vein thrombosis (Also called venous thrombo embolism . VTE ) is the most important entity .This disorder even though is a cardiovascular disease , it rarely presents to a cardiologist .

As we tended to ignore the veins for decades now, “sudden venous deaths ” other wise called massive pulmonary embolism is calling for our attention

Many times DVT is diagnosed only after it embolises into lung.So remember shortness of breath and acute dyspnea could be the first manifestation of DVT.

Once diagnosed DVT it should be risk stratified either as low risk or high risk .

Biochemical diagnosis of DVT : DVT is a form of intra vascular coagulation and it activates fibrinolysis.D Dimer estimation has strong negative predictive value .If D dimer is negative it excludes DVT by 99% .Positive D dimer does not confirm it .

Is it necessary t0 image the venous clots ?

No . It is rarely required. Instead we need to know the site of occlusion .Doppler and ultrasound scan can help locate the site of obstruction .

Other modalities * may help evaluate the thrombus

Venous angiography (Filling defect, collateral )

MR angiogram

Fibrinogen tagged nuclear scan

Management

Acute management

Long term management .

Acute management

Immediate Heparin , bolus followed by infusion ( 5000U, 1000U/h) followed by oral anticoagulation forms the corner stone of management of DVT .

Once a DVT is documented should we attempt to improve the venous circulation or try to slow down the venous circulation ?

There is a paradox here.The therapeutic strategy is to improve the venous circulation . A sluggish venous circulation predisposes fresh thrombus. So even though , it is logical to expect some migration of thrombus proximally with the standard therapeutic methods of DVT , it is the ultimate principle of management of DVT.

How heparin infusion achieves it’s therapeutic goal of clearing thrombus burden in the venous circulation is not clear .It is believed sub clinical PE occurs in every case with large DVT and these thrombi get microlysed either within focus of DVT or in transit circulation or within the pulmonary vascular bed.

What is effect of intensive anti coagulation on DVT ?

Lyses the thrombus

Dissolves the thrombus

Dislodges thrombus

It can prevent only fresh thrombus

Answer : All of the above can occur

Can we track the movement of deep vein thrombus ?

It is not an easy thing to track the movement. Doppler will give an idea. Invasive investigation to track the thrombus is neither practical nor necessary.

What is aggressive management * for DVT ?

* Aggression is rarely required in DVT management.

Interventional

Thrombolysis : Systemic/local catheter based

Venous angioplasty/Stenting

IVC filters

Surgical

Indication for thrombolytic therapy

Surprisingly, thrombolytic therapy has limited role in the management of DVT. There is absolutely no role for routine thrombolysis in DVT (Heparin does the same job , more consistently with less risk )

It is used only when there is limb threatening or lung threatening situation .

Pulmonary embolism already occured

Massive iliofemoral thrombosis .

When will you call a vascular surgeon ?

Thromboembolectomy as a treatment for DVT is rarely advocated .

The 2004 American College of Chest Physicians consensus statement on the treatment of thromboembolic disease recommended against the routine use of venous thrombectomy in acute DVT except in cases of phlegmasia cerulea dolens . ( Severe necrotising venous edema )

The issues against surgery are

Generally these patients are more sick and co morbid conditions

Complex nature of surgery in deep iliac veins

Blood loss from deep friable veins

The surgery further traumatizes the vein, recurrence of DVT is very much possible

Primary cause is not addressed by surgery

What are the indications for IVC filter ? What are the types of filter available ?

The indication for IVC filter in the acute management of DVT * has been ( Rather continues to be . . .) controversial .The major reason for the controversy is the risk ( The wasted effort too !) to benefit ratio and is not clear.

*In long term prevention of PE the indications are fairly established.

Differential diagnosis

Is there an entity called superficial venous Thrombosis (SVT)

Superficial venous thrombosis and thrombophlebitis are more common than DVT and should not be confused with DVT. ( Easier said, some confusion is bound to occur !especially , when it occurs over thighs ) .This is common following IV line and varicose veins in lower limb Present with pain, tenderness, or an indurated cord along a palpable superficial vein with erythema. It is less likely to propagate into pulmonary circulation.

How often a superficial venous thrombosis convert into deep vein thrombosis ?

Patients with superficial phlebitis above the knee have an increased risk of deep venous thrombosis and should probably have ultrasonography.They may require warm compression , NSAIDS and local thrombectomy.

What is the post-thrombotic syndrome? How to differentiate it from recurrent DVT ?

Post-thrombotic syndrome is due to the damage to the valves in the veins that leads to chronic venous edema of extremities. It may mimic like an DVT . usually occur within 2 years of DVT.

Unanswered questions

1. What will happen to the thrombus following filter insertion ?

Large thrombus gets trapped in IVC .The problem gets shifted form the legs to the vena cava .This makes it mandatory for these IVC clots to be cleared either manually or pharmacologically. Small thrombus and embolic showers continue to cross the filter without difficulty.

2. IVC filters are recommended in DVT , if a patient has an absolute contraindication to heparin but , is it not a fact , filters also demand anticoagualtion ?

It is true , filters demand anticoagulation. So , oral anticoagualtion should be given whenever possible in all even after IVC filter. This is , not only to make sure filter does not get clogged but also prevent further clot formation in the legs and also distal to the filter in (Procoagualnt ) individuals .Further , anticoagulation forms the mainstay treatment in patients with chronic thromboembolic PAH , which the filter does not address to.

3. Is there safe venous clots that the pulmonary circulation can effectively tackle ?

Intensive Heparin protocol followed by long term oral anticoagualnats (1 year or more) is an excellent approach in most patients.

The most important point to remember is the treatment for high risk DVT and suspected or established PE is exactly same

*Only 10% of PE are candidates for thrombolytic or surgical therapy so at times of real dilemma , there is nothing wrong in administering heparin in all patients with suspected high risk DVT/PE even without confirmation.

All those hi fi stuff of V/Q scan , pulmonary angiography may be a misadventure .Remember empirical (Some call it as unscientiifc ! ) therapy too , can save many lifes

Sick sinus syndrome or sinus node dysfunction (SSS, SND ) is one of the common cause of symptomatic bradycardia .The other cause for pathological bradycardia is complete heart block.Together , these two entities share 99% of indications for permanentpacemaker implantation.

The sinus node can get affected in various diseases . The commonest cause for SND is age related.This is manifested as inappropriate bradycardia .The other common presentation of SND is exaggerated bradycardia to betablockers and calcium blockers.In fact , some consider drug induced bradycardia is nothing but , unmasking of underlying SND.Pathological states that result in SND include hypothyrodism , infiltrative and inflammatory diseases . (Surprisingly , ischemic SND is a lesser clinical problem when considering the rampant CAD in our population )

What is is a fundamental difference between SND and complete heart block* ?

Sinus node is the proximal most pacemaker of the heart. When it fails the chances of a subsidiary pacemaker coming to the rescue is far greater than a complete AV block. Further the quality and stability of the escape pacemaker is better in SND. In fact , in pure SND ( With out AV nodal disease) a sinus arrest is rarely fatal as escape rhythm occur without fail.

* It should be emphasised , there can be associated AV nodal disease in significant (10%) number of patients with SND .This may be present either at the time of diagnosis or it can develop later in the course .This has important implication in the selection of pacemaker .The discussion here is confined to isolated SND .

How common is ventricular escape rhythm in SND ?

It is very rare. the ventricle never gets a chance to come to the rescue as invariably junctional pacemaker takes over at times of extreme sinus pause/arrest.For the same reason , pause dependent VT (Brady dependent ) is also less common in SND .

What is stokes Adam’s attack ? How common it is seen in SND ?

It is the cardiogenic syncope due to extreme bradycardia. This classically occurs in complete heart block , when

the the escape rhythm becomes either very slow or temporarily goes for sleep .This results in a huge pause (unlike sinus pause of , the pause here is ventricular pause , this is actually an asystole ) it can immediately trigger an VT or VF .

If SND is not life threatening why pace maker is indicated in them ?

The pacemaker is primarily indicated for prevention of dizziness , near syncope or syncope.So primary impact is on improving quality of life , not reduction in mortality. While in CHB pacemakers improve symptoms and survival.

Which form of SND can be dangerous ?

When SND is associated with rapid atrial fibrillation some times it can trigger a VT/VT if , these patients also have

a fast accessory pathway with short refractory period. (<250msec)

Final message

If you have only one pacemaker at your disposal , but there are two patients , one with SND and other with CHB please put the pacemaker to the patient with CHB , even if the later has insurance coverage and the former is not .You are justified in diverting the pacemaker !

LV dysfunction , perhaps is the most common medical term used by physicians world over.But surprisingly , It is not easy to infer what they mean by it ! The term literally means left ventricle is not functioning all right .

LV dysfunction can be classified by many ways.

Symptomatic vs Asymptomatic

Global vs Regional

Reversible vs Permanent

Systolic vs Diastolic

Ischemic vs Nonischemic

Primary vs Secondary ( Muscle vs valve etc)

If you analyse the above classification LV dysfunction can mean different things to different people , at different times.Though systolic dysfunction , as reflected by low EF % ( Less than 50% ) is the major cause of LV dysfunction the issue is not simple.

Is coronary artery disease ( CAD ) a must for LV to become dysfunctional ?

No , not at all .CAD is the leading cause of LV dysfunction .Primary muscle disorders -cardiomyopathy is an equally common entity. Valve disorders especially aortic valve stenosis is another common cause for LV dysfunction. Further , systemic hypertension, diabetes mellites, renal failure, can result in serious impairment of LV function .Some drugs ( Adriamycin ) can either precipitate or aggravate LV dysfunction.

If physicians themselves are confronted with such complexity , how are , our other medical colleagues (Forget about the patients ! ) will understand the concept of LV dysfunction.

But , the crux of the matter is every doctor believes LV dysfunction is synonymous with low ejection fraction. A surgeon or an anesthetist is quiet happy to operate if the ejection fraction is above 60% .

Yes , this can occur in advanced degrees of diastolic dysfunction, where cardiac contractility is normal but

fails to relax adequately .

Is diastolic dysfunction less dangerous than systolic dysfunction?

May be , that is the dominant opinion , but there are sufficient evidence emerging that opinion is wrong.The main reason for diastolic dysfunction to send a ” not so sinister signal ” is over diagnosis of grade 1 diastolic dysfunction in the general population . The echocardiologists considered it fashionable for a quiet a longtime (Many have changed since then !) to report all patients with reversed E :A ratio in the mitral inflow doppler profile as diastolic dysfunction. This has resulted in thousands of asymptomatic , healthy people getting labelled as grade 1 diastolic dysfunction undermining the importance of this entity.

The fact of the matter is true diastolic dysfunction is indeed dangerous , if not more dangerous than systolic dysfunction for the simple reason , there is no specific treatment for this condition

To improve the specificity to diagnose genuine LV diastolic dysfunction it is suggested to remove grade 1 diastolic dysfunction from the literature .

Other causes of LV dysfunction with normal EF

Some times , there can be wall motion defects and mitral regurgitation but still the EF can be normal .

Mitral valve dysfunction can be a part of LV dysfunction .The EF is either not affected as ischemic damage might be confined to papillary muscle.

Vigorous compensation from non ischemic areas can normalise an EF

What is the difference between LV dysfunction and LV failure ?

Many times both these terms are perceived to convey the same meaning .But it can never be used synonymously .Cardiac failure is a clinical entity while LV dysfunction is a derived technical parameter by and large an echocardiographic enity. Cardiac failure is defined classically as a clinical syndrome .(elevated jvp, edema * S 3 rales etc) Neuroueohormonal activation can occur with both.

A patient with LV dysfunction when destabilsed develops LV failure and after stabilisation of LV failure he is brought back to the baseline LV dysfunction

*What is the link between LV dysfunction and RV dysfunction ?

RV can not be silent companion when the LV fails . There always have been link between the two.

Apart from the classical concept of ventricular interdependence , where inter ventricular septum plays a pivotal role , now there is strong evidence to prove both LV and RV myocardial muscle bundles are interwoven . In fact failing LV drags the muscle bundles over RV also (Friendly pull , let us die together !) and this is classically seen in idiopathic dilated cardiomyopathy where all four chambers of the heart dilate. There is also biochemical evidence the RV myocytes deplete thier norepinephrine stores in LV failure.

Is there an entity called transient or temporary LV dysfunction ?

The classical chronic reversible LV dysfunction also called hibernating myocardium is a different topic shall be discussed later.

Can acute ischemia cause LV dysfunction ?

Yes .This can occur during ischemic stunning of myocardium during NSTEMI .This can result in acute pulmonary edema* at times.This can be termed as ischemic LV dysfunction as there is no myocardial necrosis .

Or is it simply a mechanical inability* to contract as the outflow is closed ?

There is no specific answer . All the above factors may contribute .*But the fact that most patients recover full normal LV function following aortic valve replacement would make the last explanation more likely.

What does the term LV dysfunction mean to a cardiac surgeon when he plans for a CABG ?

LV dysfunction becomes an important determinant of overall outcome in patients who are going to receive a CABG .The surgeon will have contingent strategies during peroperative and post operative phase while operating in hearts with severe LV dysfunction.

How much of LV function is going to recover after CABG ?

This can not be predicted accurately but CABG may not resucitate all dying myocytes and bring life in them .The buttressing effect of blood within the dysfunctional segement can improve contractility and reduce the wall motion defect(This is an indirect mechanism of improving EF )

The answer to this question is not easy , as one would tend to believe . In fact this question , takes it for granted revascularisation will improve the LV dysfunction in patients with severe LV dysfunction.

The truth is , we are not sure about the mechanisms . How revasculariastion will have an effect on chronically dying or dead myocardium ? (Acutely dying myocardium is a different story, where revascualrisation has a profound effect , that is called salvaging the myocardium )

This issue is of great clinical significance in end stage ischemic heart disease .A typical myocardial segment in ischemic cardiomyopathy has millions of the dead cells interwoven with dying cells with occasional clusters if live cells scattered all over .Once the process of myocardial apotosis sets in , myocardial cell death does not result in segmental destruction instead an universal cell death.(Paracrine signals of cell death that spills over to adjacent segments ) The current standards of revascualrisation (PCI and CABG) aims to provide blood flow in a segmental fashion. Even if the blood flow is restored in an obstructive vessel it is not clear , how it is going to enter the chronically atrophied myocytes.

Meanwhile , many studies are available suggesting coronary revascularisation does indeed improve LV dysfunction. These evidence has never been conclusive .Real world experience would also confirm this simple fact , that angina relief is definite following revascularisation but not dyspnea relief in patients with LV dysfunction .

So , when seeking the guidelines for revascularisation ( PCI or CABG ) in patients with CAD one need to ask this specific question

Does the patient has

A.Angina alone

B.Angina and dyspnea

C.Only dyspnea

If the answer is C , assess the patient again , rule out systemic causes of dyspnea (Anemia, renal function etc) rethink or postpone revascularisation.If primary or secondary LV muscle dysfunction has set in revascularisation has little value.

Coronary collateral circulation is the God’s gift to mankind.It has potential benefits ( and of course real benefit !) both during acute and chronic coronary syndrome.

Collaterals in CCS

The classical role of coronary collateral is in patients with chronic stable angina.It is quiet common to see patients with totally occluded LAD or RCA with normal LV function maintained by extensive collaterals .

Collaterals during ACS.

An intact and functional collateral circulation can prevent an NSTEMI from converting into STEMI.In fact many of the patients with unstable angina patients carry on with viable myocardium just because thaey have good collaterals.It gives us a time window to intervene .Some times the col laterals are good enough and help us avoid a revascularisation in toto.

Collateral’s in STEMI.

This is not well understood. Some researchers reported opening up of collateral channels very early after a STEMI. Logic would suggest , anatomically patent functionally closed collateral channels are always available at time of crisis. But not every one is blessed with such rescue mechanism.

What determines the native collateral channel development in human cor0nary circulation ?

When the answer is unknown , it moves to the genetic domain also called – God’s domain .

Our ignorance in decoding coronary collaterals is vast.

The chief cause of this ignorance is we always tend , not believe things which we don’t see.

Coronary collaterals channels need to atleast 1mm to be visualised by CAG.There could be a vast network of micro collaterals out there within the myocardium invisible to current imaging methods. (In fact , this has a link with outcome of the COURAGE study )

Is coronary collaterals have all the three layers of an artery ?

Yes .But the media lacks muscle.

Is coronary collateral less prone for spasm ?

May be.

The drugs we give , Calcium blockers , betablockers, and nitrates have same hemodyanmic effects as in native coronary circulation ?

We don,t know as yet. Nitrates are supposed to improve collateralisation

How common is atherosclerosis to involve the coronary collaterals ?

How often is an ACS precipitated by an collateral occlusion ?

May be more common than we think.

Can we stent a 2mm wide collateral to maintain the patency in case of a CTO ?

A question need to be answered by current generation interventional cardiologists.

Is coronary collateral gives protection against primary VF ?

In one sense , the number one killer of mankind is in fact not STEMI but the VF that follows it .

Why only a few develop a VF following an MI ? What determines the arrhythmic response to ischemia ?

Some anecdotal observation of suggest a role for early coronary collateral opening in the prevention of VF .

Is it a transudate or exudate ? How to confirm the pleural effusion is primarily cardiac failure related ?

When the classical protein criteria is inadequate or prone for errors

Try this more specific marker within the pleural fluid

N-Terminal Brain naruretic peptide

Pleural fluid NT-proBNP is very useful in establishing the diagnosis of HF-associated effusions, and it confirms this diagnosis . The measurement of NT-proBNP rather than serum to pleural protein gradient is recommended for identifying mislabeled cardiac transudates.